The present invention relates to methods of manufacturing foam compositions, for use in the preparation of pharmaceuticals or other chemical products. The invention further relates to syntactic foams which are deformable and/or compressible. The syntactic foam compositions of the present invention may be used as carriers, coated or uncoated for chemicals, biologicals, nutraceuticals, growth factors, amino acids, bioactive materials and pharmaceutically active and inactive materials and have pharmaceutical, sanitary, veterinary, agricultural and medical applications. The invention further relates to pharmaceutical and chemical syntactic foam compositions.
Syntactic foam is material consisting of prefabricated, manufactured xe2x80x9cbubblesxe2x80x9d or microsphere fillers in a resin milieu. Syntactic foams having industrial applications are known.
Before the advent of syntactic foams, there were generally two types of foams: blown foams created by the injection of gas; and, self-expanding foams created through the use of chemicals. More recently, materials created by mixing a solid with minute spheres of glass, ceramic, or polymer are finding an increasing range of uses in industrial and high-tech applications.
Blown foams are made by, mixing or injecting a gas into a liquid and causing it to froth like soap bubbles in a bathtub. When the bubbles solidify a foam is created. Typically, self-expanding foams require the use of at least two chemical constituents: one to decompose into a gas to form the bubbles and one to form the walls of the cells. Again, when the bubbles solidify a foam is created.
On the other hand, syntactic foams use prefabricated or manufactured xe2x80x9cbubblesxe2x80x9d such as microspheres. Some refer to the microspheres as microballoons or even macroballoons. For the purposes of this application the term microspheres is used to include all of these terms and to also include spheres filled with air and spheres which are not filled with air, although it is generally recognized that spheres filled with air are preferred for the preparation of a syntactic foam. The microspheres are mechanically combined with a resin to form a composite material. In this way, the microspheres act as scaffoldings providing structure within the composite material which is formed. The term xe2x80x9csyntacticxe2x80x9d is derived from the Greek syntaktikos, meaning xe2x80x9cto arrange togetherxe2x80x9d. Whereas blown and self-expanding foams develop a fairly random distribution of gas pockets of widely varying sizes and shapes, the porosity of syntactic foams can be much more closely controlled by careful selection and mixing of the microspheres with the resin milieu. Syntactic foams could also be called assembled foams.
While ordinary foams are visibly porous, syntactic foams can have cells so small that the material appears to be a homogeneous solid. Syntactic foams are typically used in deep-submergence vehicles, instrument packaging, electronic gear, cable buoys, floatation collars for deep-water drilling operations, radio frequency and aerospace applications, and by pattern-makers in factories. In other words, the foams are used in industrial applications where, for example, buoyancy is important.
The use of syntactic foams as carriers of coated or uncoated chemicals, biologicals, nutraceuticals, growth factors, amino acids, bioactive materials and pharmaceutically active materials for pharmaceutical, sanitary, veterinary, agricultural and medical applications is not common. Shortcomings in current methods of manufacture of syntactic foams thereby rendering them generally unsuitable for use as carriers particularly in the manufacture of pharmaceuticals include cost, difficulty of fabrication and assembly, high temperatures encountered during fabrication and toxicity of the materials used.
A review of the prior art shows that U.S. Pat. No. 3,856,721 discloses a syntactic foam produced by a controlled curing of a polymer which is a homopolymer of butadiene or a copolymer of butadiene and styrene or the like, at least 40% of which polymer is butadiene. Instead of styrene, a methyl or ethyl derivative may be used. The syntactic foam includes minute hollow spheres which give strength to the foam product and the syntactic foam product has a very low density. The polymeric material of this invention is subjected to a two-stage cure. The first stage being a low-temperature curing system utilizing methylethyl ketone (MEK) peroxide or other peroxides used in lower-temperature cures, cobalt naphthenate, iron naphthenate, and acetylacetone (pentanedione) or the like; the peroxide used in the second stage requiring a higher temperature for activation.
In U.S. Pat. No. 4,250,136, in the preferred form of the invention, a sandwich of composite materials is assembled and placed within a mold having the shape of the article to be formed. The composite sandwich is comprised of the following ingredients: (1) a first or bottom layer of reinforcing material such as fiberglass in woven or mat form; (2) a first layer of initially resilient and open-cell foam containing a liquid thermosetting resin such as epoxy, polyester, vinylester, or the like, is laid over the first reinforcing layer, (3) a second layer of reinforcing material is laid over the first resin-containing, open-cell foam layer; (4) a suitable quantity of uncured syntactic foam having a dough-like consistency is placed over the second reinforcing layer, (5) a third reinforcing layer is placed over the uncured and amorphous syntactic foam; (6) a second layer of liquid, resin-containing, open-cell, resilient foam is overlaid on the third reinforcing layer; and (7) a fourth or upper layer of reinforcing material is laid upon the second resin-containing foam layer. The composite sandwich is then placed within the mold and subjected to suitable heat and pressure to cause the uncured sandwich to assume the internal shape of the mold.
U.S. Pat. No. 4,425,441 discloses a high temperature and flame resistant closed cell polyimide foam material and methods of making the foam. An aromatic tetracarboxylic acid dianhydride is reacted with an oxontine to produce an N-substituted imide, which is then esterified with a suitable alcohol. The resulting liquid is dried and the dry residue is reduced to a uniform powder having particles with diameters generally in the 0.5 to 10 mm range. The powder is preferably further dried, either before or after final size reduction, in a moderate vacuum at moderate temperature to remove any excess residual alcohol. The powder spontaneously expands to form a closed cell foam when heated to a temperature in the range of about 90xc2x0 to 150xc2x0 C. for a suitable period. When the powder is expanded in a closed mold, a well consolidated, uniform, closed cell foam product results. When expanded in an unrestricted manner, closed cell xe2x80x9cmacroballoonsxe2x80x9d having average diameters between about 0.4 mm to 15 mm result.
U.S. Pat. No. 4,518,717 discloses methods of making low density modified polyimide/polyimide-amide foams and the resulting compositions. An N-substituted aliphatic imide is prepared by reacting a suitable aromatic dianhydride with a suitable oxime. A polyimide forming material is prepared by dissolving the N-substituted aliphatic imide in an esterifying solvent, then adding a suitable aromatic diamine. This material is dried to a powder. A suitable hydrated compound which is stable up to at least about 100xc2x0 C. is mixed with the powder. A foam is then produced by heating the material to reaction temperature for a period sufficient to produce a stable foam. The material melts, then spontaneously expands into a foam which becomes self supporting and cures to a resilient flexible foam. The addition of the hydrated compound is found to result in an exceptionally low density foam. Depending upon heating conditions, a polyimide, polyimide-amide or mixture thereof may be produced, resulting in foams having selectively variable physical properties.
Prior U.S. Pat. Nos. 4,161,477, 4,183,838 and 4,183,839 disclosed and claimed certain polyimide compositions which are flame resistant and useful as coatings and adhesives. The coating and adhesive compositions described in the above-mentioned prior patents are made by first preparing a suitable bisimide by reacting an aromatic tetracarboxylic acid dianhydride with a cyclic amide or oxime. The imidization reaction is preferably conducted at a temperature of 170xc2x0-200xc2x0 C. for 20-60 minutes. The polyimide forming material is then prepared by dissolving the bisimide in an inert solvent; then adding thereto a suitable diamine, producing a viscous fluid containing an intimate, unpolymerized mixture of N-substituted cyclic bisimide dicarboxylic acid and diamine which is capable of being converted to a high molecular weight polymer by the application of heal The solution is coated onto a surface and polymerized by heating to a temperature in the 177xc2x0-316xc2x0 C. range for 30 minutes to 5 hours.
A foamed ibuprofen-containing dosage is disclosed in German patent application 19635676. A mixed copolymer of N-vinylpyrrolidone and vinyl acetate is melted with ibuprofen. The melt is impregnated with carbon dioxide gas while being passed through an extruder. The carbon dioxide expands to yield bubbles impregnated in the melt after it exits from the extruder. This is not a syntactic foam.
According to U.S. Pat No. 5,393,528, a foam for the vaginal delivery of active materials can be prepared by mixing HPMC, glycerin, and the active ingredient, and introducing nitrogen gas while mixing to form a frothy foam. The mixture is then cast as a foamed film on a solid surface. This is not a syntactic foam.
U.S. Pat. No. 6,090,401 discloses methods of preparing an edible comestible suitable for human consumption, comprising either providing a polymeric foaming agent; optionally a non-cellulosic polysaccharide, a solvent and a therapeutically effective dose of a pharmaceutically active ingredient; admixing said polymeric foaming agent, non-cellulosic polysaccharide, solvent and pharmaceutically active ingredient; forming a foam dispersion from the admixed mixture; or a method of preparing an edible comestible suitable for human consumption, comprising dissolving a foaming agent in a solvent to yield a solution of said foaming agent, dispersing bubbles of gas in the foaming agent solution to yield a foam dispersion, drying said foam dispersion such that the dried foam dispersion has a bulk density of less than about 0.4 grams/cubic centimeter. In both cases an entrained gas is used.
It would be advantageous if suitable syntactic foams could be prepared for use as powders other suitable carriers for pharmaceutical actives and other chemical compounds. The syntactic foams found in the prior art are generally unsuitable for these purposes because of manufacturing complexities thereby increasing the costs of manufacture, the use of reagents which are not suitable for human or animal consumption, the creation of byproducts not suitable for human or animal consumption and/or the requirement for high temperatures which are likely to inactivate the activity of the pharmaceutical active or other biologicals.
A further advantage of the present invention is the ability of the syntactic foam preparations of the present invention to permit time release of pharmaceuticals in a mammal, particularly humans. It is foreseen that the preparations of the present invention could be used to reduce the frequency that a particular medicine needs to be taken. For example, certain medications presently require three or times per day dosages and the present invention may be useful in reducing the number of daily doses to two or one.
In accordance with an aspect of the present invention there is provided a syntactic foam composition that looks and behaves like a homogeneous solid. In accordance with another aspect of the present invention there is provided a syntactic foam composition suitable for use as a carrier for the delivery of one or more pharmaceuticals or other chemical. In accordance with another aspect of the present invention, there are provided methods of manufacturing these syntactic foam compositions. In accordance with a further aspect of the invention, these methods are economical and versatile manufacturing processes.
In accordance with another aspect of the present invention, there is provided syntactic pharmaceutical foam compositions which are carriers, coated or uncoated, which contain chemicals biologicals, nutraceuticals, growth factors, amino acids, bioactive materials, pharmaceutically active materials and pharmaceutically inactive materials. These compositions may be used for pharmaceutical, sanitary, veterinary, agricultural and medical applications, for example. In accordance with an aspect of the present invention, such pharmaceutical or chemical syntactic foam compositions are manufactured in accordance with the methods of the present invention.
In accordance with yet another aspect of the present invention, there is provided safe, stable, syntactic foam compositions in combination with one or more pharmaceutical actives or preparations for delivery to humans and other mammals as pharmaceutical preparations.
In accordance with an aspect of the present invention, there is provided a method of preparing a deformable syntactic foam for the delivery of a compound or chemical, the method comprising:
a) mixing together one or more homopolymer resins, one or more binders, and one or more stabilizers to form a blended mixture having a LOD of from about 1% to about 10%; and
b) reacting the blended mixture with one or more organic solvents under conditions of high shear at temperatures of from about 10xc2x0 C. to about 25xc2x0 C. until a foam composition is formed wherein the foam composition is deformable to the touch. A method of manufacturing a pharmaceutical carrier, the method comprising the steps of:
a) mixing together:
i) one or more pharmaceutically acceptable homopolymer resins;
ii) one or more pharmaceutically acceptable binders;
iii) pharmaceutically acceptable microspheres, or other suitable scaffolding element, and
iv) one or more pharmaceutically acceptable stabilizers to form a blended mixture having an LOD of from about 1% to about 10%;
b) reacting the blended mixture with one or more pharmaceutically acceptable organic solvents under conditions of high shear at temperatures of from about 10xc2x0 C. to about 25xc2x0 C. until a foam composition is formed wherein the foam composition is deformable to the touch; and
c) reducing the size of the deformable syntactic foam to permit reassembly into a shaped composite.
In accordance with another aspect of the present invention, the mixture in step (a) further comprises a particulate substance which can act as a scaffolding. By the term scaffolding what is intended is that the particulate substance provide a certain regularity and/or strength to the resultant foam composition.
In accordance with another aspect of the present invention, the particulate substance is substantially spherical. Under the conditions of the present invention, the substantially spherical particles align themselves with a certain regularity or ordered arrangement of linear arrays. Advantageously, substantially spherical particles have the added benefit that they may be created to contain a medication or provide a point of binding, covalent or otherwise, for a compound, molecule or medicine which is to be distributed within the composition for subsequent delivery to a system or to a living organism.
In a particularly preferred embodiment the substantially spherical substance comprises substantially spherical microparticles such as microspheres. Microballoons is another term used in the art. There is little distinction to be made between these two terms other than the possible connotation that microballoons have a substantial air space within them whereas a microsphere may not, and also others skilled in the art may consider microballoons to be of a slightly larger size than microspheres. In the present application the term microsphere is used to include all substantially spherical microparticles such as microballoons, macroballoons or other similar elements and/or terminology as used in the art.
The regularity of spherical particles such as microspheres or microballoons is such that under the method steps of the present invention the substantially spherical particles tend to align and form groupings with regularly spaced interstices between the microparticles. When the foam composition as prepared by the method of the present invention is used as a carrier for a compound, molecule or medicine, the interstices may trap the compound, molecule or medicine. The entrapment of the medicine either distinct from, or in addition to, may be used to facilitate time release of the compound, molecule or medicine from the composition preparation.
In a preferred embodiment of the present invention, the particles have a diameter of about 1000 micrometers, or less. In a particularly preferred embodiment the particles are microspheres having a diameter of about 1000 micrometers, or less.
In accordance with another aspect of the present invention, the loss on drying (LOD) is checked intermittently during the mixing under high shear. In accordance with a preferred embodiment of the present invention, when the LOD of the reacted mixture is from about 2 percent to about 25 percent the mixing under high shear conditions is stopped. It is in this LOD range that a preferred foam composition is made by the methods of the present invention.
In accordance with another aspect of the present invention, the foam composition as prepared by the methods of the present invention may be milled or otherwise broken down into smaller particle sizes. If microspheres or other substantially spherical particles are present in the composition it may have a stringy or dendritic look to the particles as they are separated. This reflects the tendency of the microspheres to form arrays during the method steps of the present invention.
A compound, chemical or medicine may be added to the microspheres or as part of the blended mixture before high shear treatment. Alternatively, after the method of the present inventions are complete and a syntactic deformable composition has been created, a compound, chemical or medicine may be added at the end with or without breaking down the foam. The compound, chemical or medicine could be bound to the scaffolding elements, e.g. microspheres, or it could be retained for a shorter period of time in the interstices of between the microspheres. The interstices are the spaces formed by abutting microspheres.
In accordance with another aspect of the present invention. The syntactic foam composition of the present invention may be shaped into a shaped composite after the foam is created. A variety of shapes may be used depending on the ultimate usage of the product. The composition may also be used in other preparations as well.
In accordance with an aspect of the present invention, the preferred stabilizer is silicic anhydride.
In accordance with an aspect of the present invention, the preferred organic solvent is 2-propanol.
In accordance with an aspect of the present invention, the preferred homopolymer resin is a carboxyvinyl polymer.
In accordance with an aspect of the present invention, the preferred the microspheres are selected from the group consisting of silica, sucrose, glucose, lactose, dextrose, sorbitol, mannitol, xylitol, dextrates, poly(lactic acid), poly(glycolic acid), poly(glycolic acid-co-lactic acid), poly(xcex5-caprolactone), poly(malic acid), cellulose, microcrystalline cellulose, metal, glass and small beads.
In accordance with an aspect of the present invention, the preferred method according to any one of the above claims wherein the blended mixture further comprises a binder as part of the blended mixture.
In accordance with an aspect of the present invention, the preferred binder is selected from the group consisting of high molecular weight polysaccharide, xanthan gum, d-xcex1-tocopherol polyethylene glycol 1000 succinate, starch NF, povidone, copolyvidone NF, polyvinyl alcohols, glyceryl behenate, xanthan gum, polyethelene glycols, polyethelene oxides, cellulose binders, hydroxypropyl Methylcellulose USP and hydroxyethyl Cellulose NF.
In accordance with an aspect of the present invention, the preferred binder is a high molecular weight polysaccharide, more preferably a Xanthan gum and yet more preferably a d-xcex1- tocopherol polyethylene glycol 1000 succinate.
In accordance with another aspect of the present invention, the deformable syntactic foam prepared by the methods of the present invention is reduced in size by drying (LOD less than about 5%) and then milling before shaping into a composite for use as a carrier or use in a chemical or pharmaceutical composition.
In accordance with another aspect of the present invention, there is provided a composition comprising a chemical, compound or medicine such as a pharmaceutical together with a carrier made by the methods of the present invention.
In accordance with another aspect of the present invention there is provided a composition comprising a chemical, compound or medicine together with a syntactic foam prepared in accordance with the methods of the present invention.
In accordance with a preferred embodiment of the present invention, there is provided a composition comprising a pharmaceutical is selected from the group consisting of human and veterinary medicines and a syntactic foam prepared in accordance with the methods of the present invention.
In accordance with another aspect of the present invention, the compositions of the present invention further comprise the preparation step of applying a coating agent to the foam before a size reduction step or after a shaped composite is prepared.
In accordance with another aspect of the present invention, the pharmaceutical compositions of the present invention are suitable for use in time release or controlled release preparations.
In accordance with another aspect of the present invention, the pharmaceutical used in the compositions of the present invention is either an active or else an inactive metabolite of an active pharmaceutical ingredients or salts of the metabolites of active pharmaceutical ingredients.
In accordance with another aspect of the present invention, the compositions of the present invention comprise a pro-drug which after oral administration generates active or inactive metabolites.
In accordance with another aspect of the present invention, the compositions of the present invention comprise a precursor chemical or compound which after oral administration to an animal or a human generates either pharmaceutically active or inactive metabolites.
In accordance with another aspect of the present invention, the pharmaceutical compositions of the present invention further comprise according to any one of become systemically available over a period of not less than two hours after administration to a human or other mammal.
In accordance with another aspect of the present invention, the pharmaceutical compositions of the present invention are time-released or controlled release preparations.
In accordance with another aspect of the present invention, the compositions of the present invention, elicit pharmacological or therapeutic activity.
Other and further advantages and features of the invention will be apparent to those skilled in the art from the following detailed description thereof taken in conjunction with the accompanying drawings.